High Programmed Death-Ligand 1 Expression is Associated With a Shorter Progression Free Survival in ALK-Rearranged Lung Cancer Patients Treated With First Line Tyrosine Kinase Inhibitors

Abstract

Background: Although ALK-positive non-small cell lung cancer (NSCLC) derives limited benefit from immune checkpoint inhibitors, PD-L1 expression is frequently elevated at diagnosis. The clinical relevance of PD-L1 expression for the efficacy and durability of response to ALK tyrosine kinase inhibitors (TKIs) remains unclear. We investigated the association between tumor PD-L1 expression and outcomes with first-line ALK TKIs and used complementary preclinical models to explore potential biological mechanisms.

Methods: Clinical, pathologic, molecular, and treatment outcomes were evaluated among patients with ALK-rearranged NSCLC treated at the University of Colorado. PD-L1 expression was assessed by tumor proportion score (TPS). Murine EML4-ALK lung cancer cell lines were engineered to overexpress PD-L1, and effects on ALK TKI response were evaluated in vitro and in immune-competent mouse models.

Results: Among 130 TKI-naïve patients treated with first-line ALK TKIs, 57 (44%) had high PD-L1 expression (TPS ≥ 50%). After multivariable adjustment, high PD-L1 expression was associated with significantly shorter progression-free survival (PFS) compared with low PD-L1 expression (11 vs. 21 months; HR 2.29, 95% CI, 1.51-3.49; P ≤ .001), with no difference in overall survival (91 vs. 107 months; HR 1.16, 95% CI, 0.62-2.17). Objective response rates were similar between PD-L1-high and -low tumors (81.8% vs. 83.3%; Pearson r = -0.20, 95% CI, -0.40-0.07). In preclinical EML4-ALK models, tumor cell PD-L1 overexpression did not alter alectinib sensitivity, depth, or durability of response in vitro or in vivo CONCLUSIONS: High PD-L1 expression is associated with shorter PFS to first-line ALK TKIs without affecting the initial radiographic response. Preclinical findings suggest that PD-L1-intrinsic tumor cell signaling does not directly impair ALK TKI efficacy, implicating tumor microenvironment-mediated mechanisms in reduced response durability.

Keywords: Anaplastic lymphoma kinase; NSCLC; PD-L1; Prognosis; TKI.